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This paper utilizes a sender-receiver game involving a government and infinite heterogeneous agents to analyze the characteristics of information transmission in an environment where a true state does not exist and coordination among various players is required. It shows that a message conveyed by the government induces agents to consider public opinion not through direct communication, but through expectations concerning the government's action. It also shows that the need for coordination, self-interest, and altruism enable the government to convey a more precise and credible message by decreasing the incentive to misrepresent information, whereas a perfectly altruistic government would always convey a precise message.

Background: Right ventricular (RV) dysfunction contributes to poor prognosis in patients with pulmonary hypertension. Although pulmonary artery banding (PAB) induces RV inflammation, its mechanisms are poorly understood. Hypothesis: We assessed the hypothesis that RV pressure overload induced by PAB leads to RV dysfunction through NF-κB-mediated inflammation and fibrosis. Methods and Results: We banded the main PA using an 18-gauge needle in adult Sprague-Dawley rats (BW: 180-220g). We measured hemodynamics and analyzed immunohistochemistry of RV at Day 1, 3, 7 and 14 after PAB (n=4-6, each group). PAB time-dependently increased RV systolic pressure (sham: 31.1±5.7 vs. Day14: 73.2±11.8mmHg, p Conclusions: These findings indicate that PAB immediately activates NF-κB and increases macrophage infiltration. Second, chronic treatment with PDTC attenuates NF-κB activation and macrophage infiltration in RV, leading to reduced fibrosis as well as RVEDP. NF-κB inhibition may be a therapeutic target for the RV dysfunction.

O shunt portossistemico ou desvio portossistemico (DPS) sao comunicacoes vasculares unicas ou multiplas entre a circulacao sistemica e a circulacao portal, que permite que o sangue portal chegue ao sistema circulatorio sem antes passar pela metabolizacao hepatica. Podem ser adquiridos ou congenitos e tambem podem ser classificados como intra-hepatico, localizado dentro do figado, ou extra-hepatico, localizado fora do parenquima hepatico. A forma adquirida normalmente esta associada com disturbios intra-hepaticos. Eles normalmente sugerem vasos tortuosos que se comunicam com a veia cava caudal na regiao do rim esquerdo. A forma congenita esta associada a genetica e uma das linhagens mais acometidas e a raca maltes. O presente relato de caso descreve o diagnostico e tratamento de uma cadela maltes de oito meses de idade com Shunt portossistemico extra-hepatico. A paciente apresentava sinais de encefalopatia hepatica, como: inquietacao, locomocao apoiando-se nas paredes, compressao da cabeca contra a parede, tremores de cabeca e deficiencia visual. Exames complementares constataram: glicemia pos-prandial proximo do valor inferior de referencia, fosfatase alcalina (FA) e alanina aminotransferase (ALT) aumentadas e hipoalbuminemia. A ultra-sonografia revelou a presenca de calculo vesical e calculo renal bilateral, figado diminuido e aumento da ecogenicidade, vesicula biliar com conteudo anecoico e alta celularidade podendo sugerir hepatopatia/ colangiohepatopatia e detectou DPS extra-hepatico. O uso do Doppler auxiliou na localizacao do desvio identificando a comunicacao e a turbulencia certificando-se do DPS extra-hepatico. Dieta com restricao proteica e antibioticoterapia com amoxicilina obtiveram bons resultados. Optou-se em fazer apenas o tratamento clinico e manter a qualidade de vida da paciente.

The shunt portosystemic or portosystemic deviation (PSD) are unique or multiples vascular communications between the systemic circulaton and the portal circulation, that permit blood flow reaches the circulatory system without first passing trhought the hepatic metabolization. May be acquired or congenital and can also be classified as intrahepatic located within the liver or extrahepatic located outside the liver parenquima. The acquired form is usually associated with intra-hepatic disorders. They usually suggest tortuous vessels that communicate with the caudal vena cava in the region of the left kidney. The congenital form is associated with genetic lineage and one of the most affected is Maltese breed. This case report describes the diagnostis and treatment of a eight year-old female Maltese dog presenting extrahepatic Portosystemic Shunt. The patient showed signs of hepatic encephalopathy, such as restlessnees, weakness, deambulation, head tremor and impaired visual. Complementary exam demonstrated: postprandial glicemia near the lower limit of reference, alkaline phosphatase (ALP) and alanine aminotransferase (ALT) increased and hipoalbuminemia. Ultrasonography revealed the presence of vesical calculus and bilateral kidney, liver decreases and increased echogenicity, gallbladder with anechoic content and high cellularity may suggest liver/ colangiohepatopatia and extrahepatic DPS was detected. The use of Doppler assisted in identifying the location of the bypass communication and the turbulence detecting the extrahepatic DPS. Protein-restricted diet and antibiotic therapy with amoxicillin achieved good results. The clinical treatment was decided make only the clinical and maintain the quality of life of the patient.O shunt portossistêmico ou desvio portossistêmico (DPS) são comunicações vasculares únicas ou múltiplas entre a circulação sistêmica e a circulação portal, que permite que o sangue portal chegue ao sistema circulatório sem antes passar pela metabolização hepática. Podem ser adquiridos ou congênitos e também podem ser classificados como intra-hepático, localizado dentro do fígado, ou extra-hepático, localizado fora do parênquima hepático. A forma adquirida normalmente está associada com distúrbios intra-hepáticos. Eles normalmente sugerem vasos tortuosos que se comunicam com a veia cava caudal na região do rim esquerdo. A forma congênita está associada a genética e uma das linhagens mais acometidas é a raça maltês. O presente relato de caso descreve o diagnóstico e tratamento de uma cadela maltês de oito meses de idade com Shunt portossistêmico extra-hepático. A paciente apresentava sinais de encefalopatia hepática, como: inquietação, locomoção apoiando-se nas paredes, compressão da cabeça contra a parede, tremores de cabeça e deficiência visual. Exames complementares constataram: glicemia pós-prandial próximo do valor inferior de referência, fosfatase alcalina (FA) e alanina aminotransferase (ALT) aumentadas e hipoalbuminemia. A ultra-sonografia revelou a presença de cálculo vesical e cálculo renal bilateral, fígado diminuído e aumento da ecogenicidade, vesícula biliar com conteúdo anecóico e alta celularidade podendo sugerir hepatopatia/ colangiohepatopatia e detectou DPS extra-hepático. O uso do Doppler auxiliou na localização do desvio identificando a comunicação e a turbulência certificando-se do DPS extra-hepático. Dieta com restrição protéica e antibioticoterapia com amoxicilina obtiveram bons resultados. Optou-se em fazer apenas o tratamento clínico e manter a qualidade de vida da paciente.

We analyzed the relationship between the clinical characteristics, comorbidity, average relative dose intensity (aRDI) and outcome in patients of over 75 years old with malignant lymphoma. Of the 98 patients studied, the mean age was 79.9 years, and 68 patients (69.4%) had B-cell lymphomas, corresponding to mainly diffuse large B-cell lymphoma. The 5-year overall survival rate was 32.2% in 97 malignant lymphoma patients. T/NK subtype, poor performance status (PS) and high-intermediate/high international prognostic index (IPI) were found to be predictive of significantly poorer overall survival, as is the case in young patients. Correlation between comorbidity index and survival rate was not observed. We also analyzed the aRDI of cyclophosphamide and pirarubicin for 64/97 patients. The proportion of patients receiving ≤84% of the planned DI during five cycles gradually increased. Most patients could not maintain aRDI ≥85%. However, overall survival was not significantly different between patients with aRDI ≥0.85 and those with aRDI ≤0.84. In conclusion, the prognoses of very elderly patients with malignant lymphoma were not so poor when they were appropriately treated with modification of the applied dose and the duration of chemotherapy according to their status.

Undifferentiated carcinoma of the pancreas is a rare malignant epithelial neoplasm with a significant component showing no particular differentiation such as keratinization, glandular structure, or mucin production. Clinical recognition of this neoplasm is important because of its poor prognosis with a mean survival of 5 months. The primary diagnostic challenge for surgical pathologists is to distinguish undifferentiated carcinoma from poorly differentiated epithelial, mesenchymal, germ cell, hematopoietic, and other neoplasms. In addition to the morphological characteristics, immunohistochemical analyses are useful for differential diagnosis. In this article, we present a case of undifferentiated carcinoma of the pancreas, followed by a discussion focused on the differential diagnosis of undifferentiated carcinoma, as well as histomorphologic/cytomorphologic, ultrastructural, and immunophenotypic findings helpful for the diagnosis.

Aims: Despite a range of research on gender identity disorder (GID), at present there is no scientific consensus on whether the etiology of GID is mental or physical. In particular recent advances in the technology of neuroimaging research have led to an increased understanding of the biological basis of various mental disorders. GID also should be evaluated from this perspective. The aim of the present study was therefore to do the first trial to examine the regional cerebral blood flow (rCBF) in GID. Methods: Persons considered biologically male fulfilling the GID criteria are termed male to female (MTF) and, conversely, persons considered biological female are termed female to male (FTM). We compared 11 FTM subjects and nine age- and handedness-matched female control subjects. None of the subjects was regularly taking medication and none had any kind of physical or psychiatric comorbidity. To evaluate rCBF in GID subjects and control subjects, statistical parametric mapping analysis of 99mTc-ethyl-cysteinate dimer single-photon emission computed tomography was used. Results: GID subjects had a significant decrease in rCBF in the left anterior cingulate cortex (ACC) and a significant increase in the right insula compared to control subjects. Conclusions: The ACC and insula are regions that have been noted as being related to human sexual behavior and consciousness. From these findings, useful insights into the biological basis of GID were suggested.

A 67-year-old Japanese woman who presented with erythema on the abdomen and pancytopenia was found to have acute promyelocytic leukemia (APL). A skin biopsy revealed invasion of APL cells. She was started on induction treatment with all-trans retinoic acid (ATRA) at 45 mg/m(2). On day 4, the leukemic cell number had increased to over 1.0 x 10(9)/L. Consequently, chemotherapy with idarubicin and cytarabine was initiated. On day 10, dryness of the lips appeared. The lower lip swelled and developed painful black eschars. A high fever was also present. Despite discontinuing ATRA on day 20 and administering antibiotics, an anti-fungal agent and valaciclovir, these signs did not improve. Histopathologically, the biopsied lip revealed infiltration of neutrophils and vasculitis. The patient was given ATRA on days 29 and 30 due to an increase in APL cell numbers, after which the gangrenous cheilitis extended over the whole lip. On day 49, the patient was started on re-induction treatment with arsenic trioxide. She achieved complete remission and the gangrenous cheilitis slowly healed over the following 8 weeks. Since the clinical features of the gangrenous cheilitis in this case were similar to those of ATRA-associated scrotal ulcers, it appears that activated neutrophils derived from differentiated APL cells may have caused the gangrenous cheilitis. Physicians should be alert to the development of gangrenous cheilitis during treatment with ATRA.

Intraductal oncocytic papillary neoplasm is known as a distinct subtype of intraductal papillary mucinous neoplasm of the pancreas. Similar neoplasms of the bile duct are rarely reported, and their disease characteristics are not well established. In this study, we examined 6 cases of biliary neoplasms consisting of oncocytic cells with almost exclusively intraductal growth. The patients were 5 women and 1 man of 51 to 68 years. Grossly, 4 appeared to be cystic neoplasms with papillary projections located in the liver and the other two were papillary neoplasms of the dilated hilar bile duct that ranged from 1.5 to 16 cm in size. The most prominent neoplastic cells were cuboidal epithelial cells that showed abundant eosinophilic granular cytoplasm with strongly positive staining for antimitochondrial antibody. Four neoplasms were mixed with minor components of nononcocytic cells. All neoplasms showed arborized papillary and/or cribriform formations except one, which showed a villous architecture. All neoplasms were adenocarcinomas accompanied by a microscopic minimally invasive carcinoma. The oncocytic neoplastic cells, as well as the nononcocytic cells, produced gastric-type mucin (MUC5AC and MUC6) and showed claudin18 and HepPar-1 positivity. Five patients lived disease-free for 10 to 112 months after resection, and 1 died of tumor recurrence at 26 months postoperatively. The present series of biliary tumors are intraductal papillary neoplasms with oncocytic features and can be clinicopathologically regarded as counterparts of pancreatic intraductal oncocytic papillary neoplasm. Our results also suggest that oncocytic changes occur in epithelial cells of biliary tracts that show a predominant gastric phenotype.

Buckwheat is used for various foods in the world. The objective of the present study is the determination of the chemical structure of a product formed in the acidic mixture of buckwheat dough and saliva that contains both nitrite and thiocyanate. In the mixture, an oxathiolone derivative of rutin, 5,7-dihydroxy-2-(7-hydroxy-2-oxobenzo[d][1,3]oxathiol-4-yl)-4H-chromen-4-one-3-O-β-rutinoside, was found. This compound seemed to be formed by the hydrolysis of a 2′-thiocyanate derivative of rutin, which was produced by the reaction of thiocyanate with the o-quinone generated by nitrous acid-dependent oxidation of rutin. Importance of the formation of the oxathiolone compound is discussed in relation to scavenging of the toxic quinone in the stomach.

Purpose : To access the necessity of topical steroids after uneventful cataract surgery, phaco-emulsification/aspiration plus intraocular lens (PEA+IOL) implantation. Design : Single-blind, randomized, prospective study. Participants : Twenty-one patients were prospectively randomized, 11 patients were assigned to the steroid group, and 10 to the non-steroid group. Methods : Between March and September 2007, in Mino Tanaka Hospital in Tokushima Prefecture, Japan, we performed PEA+IOL in 28 eyes of 21 patients and examined the visual acuity, corneal endothelium cell density, and anterior aqueous flare value after dividing all the patients into 2 groups, the topical steroid use and the non-steroid group. Results : At 1 month postoperatively, no difference was observed between the 2 groups in terms of the outcomes described, and no cystoid macular edema was detected. Conclusion : Topical steroid medication may not be absolutely essential after uneventful PEA+IOL. J. Med. Invest. 56 : 11-15, February, 2009

肥満は通常body mass index (BMI) によって判定されるが, 本来肥満は脂肪細胞過多である。そこで本研究では生活習慣病患者166名を対象に, BMIとbioimpedance analysis (BIA) 法による体組成の関係を検討した。BMIは体脂肪量と, 相関係数0.914と強く相関したが, 除脂肪量とは相関係数0.434と中等度にとどまり, BMIと除脂肪量の相関係数は, BMI≧25 kg/m2群ではBMI

After taking alcoholic beverages, the ethanol is mixed with saliva and then gastric juice. As pH of gastric juice is around 2, the ethanol might be transformed to ethyl nitrite in the stomach by reacting with salivary nitrite. In this study, reactions between ethanol and nitrite in acidified saliva were investigated. The result indicates that nitrite in acidified saliva reacted with ethanol producing ethyl nitrite. It is discussed that ethyl nitrite might be formed in the stomach after drinking alcoholic beverages and that the ethyl nitrite might function as a donor of NO in intestinal and gastric tissues.

The purpose of the present study was to review the prescription patterns of antidepressants in different countries in East Asia. The survey was conducted in China, Japan, Korea, Singapore and Taiwan from October 2003 to March 2004 using the unified research protocol and questionnaire. Twenty teaching hospitals and major psychiatric hospitals participated and a total of 1898 patients receiving antidepressants were analyzed. The survey provided a number of interesting characteristics on the prescription patterns of antidepressant in East Asia. Out of 56 antidepressants listed in the Anatomical Therapeutic Chemical Classification (ATC) index by the World Health Organization (WHO) Collaborating Center for Drug Statistics Methodology (Oslo), only 26 antidepressants were prescribed in participating countries in East Asia. On average 38.4% of prescriptions of antidepressants were for patients with diagnoses other than depressive disorders. The availability and commonly prescribed antidepressants varied greatly by country. The selective serotonin re-uptake inhibitors (SSRI) and other newer antidepressants were prescribed in approximately 77.0% of all cases. At the time of the survey, only two SSRI medications were available in Japan. However, five types of SSRI were available and were often prescribed in Korea.

Nitrite and SCN(-) in saliva can mixes with H(2)O(2) in the stomach. The mixing can result in the formation of ONOOH. It is not yet known how salivary SCN(-) reacts with ONOOH. An objective of the present study was to elucidate the reaction between ONOOH and SCN(-). In nitrite/H(2)O(2) systems at pH 2, SCN(-) inhibited the consumption of nitrite and the formation of O(3)(-). SCN(-) enhanced the decomposition of ONOOH and H(2)O(2) in HNO(2)/H(2)O(2) systems. Accompanying the reactions, sulfate was formed, suggesting that ONOOH oxidized SCN(-). SCN(-) inhibited the nitration of phenolics induced by HNO(2)/H(2)O(2). The inhibition is discussed taking SCN(-)-dependent reduction of ONOOH to HNO(2) into consideration. SCN(-) also inhibited H(2)O(2)-induced consumption of nitrite and nitration of phenolics in acidified saliva. The result obtained in this study suggests that salivary SCN(-) can reduce ONOOH to O(2)(-)/HNO(2) inhibiting nitrating reactions in the stomach.

We successfully managed two fetuses complicated with suspected airway obstruction after birth by the EXIT (ex utero intrapartum treatment) procedure, whose placental circulation was maintained till their airway was secured during the cesarean section. The first fetus was suspected to have airway obstruction due to a large neck mass. At 36 weeks of gestation, the EXIT procedure was undertaken performing the tracheal intubation successfully by laryngoscope. The second fetus with micrognathia was expected to have airway obstruction after birth. The EXIT procedure was undertaken at 35 weeks of gestation. The tracheal intubation by laryngoscope or by stylet scope was impossible, and the airway was secured by tracheostomy. The direct roles of anesthesiologists in the EXIT procedure are to let the uterus relax enough, deal with bleeding, and manage the fetal airway. The EXIT procedure is a specialized operation in which various specialists are involved, and a variety of judgments are necessary within a short time. Therefore, all concerned personnel should discuss previously to make a concensus on the processes during the procedure. The organization may be also an important role of the anesthesiologists in the EXIT procedure.

Aims An important pathogenic mechanism in the development of idiopathic pulmonary arterial hypertension is hypothesized to be a cancer-like cellular proliferation independent of haemodynamics. However, because the vascular lesions are inseparably coupled with haemodynamic stress, the fate of the lesions is unknown when haemodynamic stress is eliminated. Methods and results We applied left pulmonary artery banding to a rat model with advanced pulmonary hypertension to investigate the effects of decreased haemodynamic stress on occlusive vascular lesions. Rats were given an injection of the VEGF blocker Sugen5416 and exposed to 3 weeks of hypoxia plus an additional 7 weeks of normoxia (total 10 weeks) (SU/Hx/Nx rats). The banding surgery to reduce haemodynamic stress to the left lung was done at 1 week prior to (preventive) or 5 weeks after (reversal) the SU5416 injection. All SU/Hx/Nx-exposed rats developed severe pulmonary hypertension and right ventricular hypertrophy. Histological analyses showed that the non-banded right lungs developed occlusive lesions including plexiform lesions with marked perivascular cell accumulation. In contrast, banding the left pulmonary artery not only prevented the development of but also reversed the established occlusive lesions as well as perivascular inflammation in the left lungs. Conclusion Our results indicate that haemodynamic stress is prerequisite to the development and progression of occlusive neointimal lesions in this rat model of severe pulmonary hypertension. We conclude that perivascular inflammation and occlusive neointimal arteriopathy are driven by haemodynamic stress.

Background and Aims A side-port needle has been developed to improve diagnostic accuracy by obtaining more cellular material during EUS-guided FNA (EUS-FNA). We compared the accuracy rate of histology and the quality of histologic specimens from 22-gauge (G) side-port and standard needles for EUS-FNA of a solid pancreatic mass in a multicenter, prospective, randomized control trial. Methods Between January 2013 and September 2013, 160 consecutive patients with a suspected solid pancreatic mass at 5 tertiary referral centers were enrolled. Patients were randomized to the 22G side-port needle or 22G standard needle group. The primary endpoint was the diagnostic accuracy of histology. Secondary endpoints were the quality of the histologic specimen (quantity of tissue, degree of GI contamination, and amount of blood). Results An analysis of 154 patients (side-port, 76, vs standard, 78) was performed. Six patients were excluded because of no pancreatic mass on EUS. There was no significant difference in the rate of diagnostic accuracy of histology (side-port, 87% [66/76], vs standard, 82% [64/78]; P = .51). Samples that enabled histologic interpretation were obtained in 64% (47/73) and 43% (33/77) of patients from the side-port and standard groups, respectively ( P = .009). No significant difference was seen in the degree of GI contamination and amount of blood between groups. Conclusions There was no significant difference in the accuracy rate of histology between needle types. The side-port needle was superior to the standard needle in terms of obtaining samples that enabled histologic interpretation.

Pulmonary hypertension (PH) induced by pulmonary tumor thrombotic microangiopathy (PTTM) can be fatal because its rapid progression confounds diagnosis, and it is difficult to control with therapy. Here we describe a woman with symptomatic PTTM-PH accompanying gastric cancer that was suspected from perfusion scintigraphy. PTTM-PH was diagnosed by gastroesophageal endoscopy and lung biopsy after partial control of PH using the platelet-derived growth factor (PDGF) receptor (PDGFR) tyrosine kinase inhibitor, imatinib. Treatment with sildenafil and ambrisentan further decreased PH, and she underwent total gastrectomy followed by adjuvant TS-1 chemotherapy. PH did not recur before her death from metastasis. Postmortem histopathology showed recanalized pulmonary arteries where the embolized cancer masses disappeared. PDGF-A, -B, and PDGFR-α, β expression was detected in cancer cells and proliferating pulmonary vascular endothelial cells. Thus, PTTM-PH was successfully controlled using a combination of imatinib, drugs to treat pulmonary arterial hypertension, and cancer management.

The Japanese encephalitis (JE) zoonotic vaccine strain ML-17 was sequenced and compared to related JE virus strains to identify genomic attenuation markers. Relative to its parental strain, JaOH0566, 25 nucleotide alterations and 10 amino acid changes to, prM/M(2), NS2A(1), NS4B(3) and NS5(4) proteins were recorded. Both structural-gene changes were in the prM/M region (127Met-->Ile and 274Asn-->Thr). To study the effects of these prM/M changes, mutants bearing the changes were prepared using an infectious clone of JaOArS982 previously established at this lab. Compared with JaOArS982, mutant 127(Met-->Ile) showed marked reduction in murine neuroinvasiveness. Mutant 274(Asn-->Thr), showed slight reduction. Neither mutant recorded ML-17-equivalent attenuation, implying that prM/M changes need to combine with other recorded genomic differences to cause attenuation. Importantly, ML-17 with its unchanged E region, presents a possible backbone candidate for preparation of "E-replacement" type live attenuated flavivirus chimeric vaccines.

O uso de animais em experimentação, no âmbito das atividades de ensino ou de pesquisa científica no Brasil, encontra-se respaldado pela Lei n. 11.794, de 2008, pelo Decreto n. 6.899, de 2009, e pelas resoluções normativas do Conselho Nacional de Controle de experimentação Animal. A Universidade Norte do Paraná (Unopar) criou o Comitê de Ética para Uso de Animais (CEA) no ano de 2007, com regulamento em consonância com as diretrizes e legislações vigentes. Está constituído para analisar, deliberar e acompanhar as atividades de ensino, pesquisa e extensão que envolvam o uso de animais. Em 2011, o CEA- Unopar foi cadastrado no sistema CIUCA (Cadastro de Instituições de Uso de Animais) do Conselho Nacional de Controle e Experimentação Animal (CONCEA) do Ministério da Ciência e Tecnologia. O CEA-Unopar mantém atualizadas todas as informações e relatórios solicitados pelo CIUCA. Este trabalho tem como objetivo contribuir na promoção de informações do cumprimento das normas relativas à utilização humanitária de animais com finalidade de ensino e pesquisa científica para consolidação do CEA- Unopar.

Hemophagocytic syndrome (HPS) is a potentially fatal syndrome of dysregulated immune activation characterized by severe clinical manifestations such as pancytopenia, high fever and hepatosplenomega...

Mechanical stress activates various hypertrophic responses, including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Stretch activated extracellular signal–regulated kinases partly through secreted humoral growth factors, including angiotensin II, whereas stretch-induced activation of c-Jun NH 2 -terminal kinases and p38 MAPK was independent of angiotensin II. In this study, we examined the role of integrin signaling in stretch-induced activation of p38 MAPK in cardiomyocytes of neonatal rats. Overexpression of the tumor suppressor PTEN, which inhibits outside-in integrin signaling, strongly suppressed stretch-induced activation of p38 MAPK. Overexpression of focal adhesion kinase (FAK) antagonized the effects of PTEN, and both tyrosine residues at 397 and 925 of FAK were necessary for its effects. Stretch induced tyrosine phosphorylation and activation of FAK and Src. Stretch-induced activation of p38 MAPK was abolished by overexpression of FAT and CSK, which are inhibitors of the FAK and Src families, respectively, and was suppressed by overexpression of a dominant-negative mutant of Ras. Mechanical stretch–induced increase in protein synthesis was suppressed by SB202190, a p38 MAPK inhibitor. These results suggest that mechanical stress activates p38 MAPK and induces cardiac hypertrophy through the integrin-FAK-Src-Ras pathway in cardiac myocytes.

Background EUS-guided FNA (EUS-FNA) has become the most efficacious way to obtain specimens from a solid lesion adjacent to the GI tract. Previous reports regarding the use of a stylet during EUS-FNA were all based on cytological diagnosis and have showed no significant superiority in terms of diagnostic yield. Objective To clarify the noninferiority of EUS-FNA without a stylet (S−) compared with EUS-FNA with a stylet (S+) on histological assessment. Design A prospective, single-blind, randomized, controlled crossover study. Setting Five tertiary referral centers in Japan. Patients Patients referred for EUS-FNA of a solid lesion. Intervention EUS-FNA S+ and S− in a total of 4 alternate passes with randomization to S+ first or S− first. Main Outcome Measurements The primary endpoint was the acquisition rate of an appropriate and sufficient specimen for histological assessment. The secondary endpoints were cellularity, contamination, bloodiness, diagnostic ability, and diagnostic accuracy. Results We enrolled 107 patients (110 lesions) and analyzed 220 specimens each in the S+ and S− groups. The acquisition rate of appropriate and sufficient specimens in the S+ group was 121 of 220 (55.0%) and 122 of 220 (55.5%) in the S− group. The difference in the acquisition rate of the specimen (S− minus S+) based on the generalized estimating equation was 0.42% (95% confidence interval, −6.72% to 7.56%), which was less than 10% of the prespecified noninferiority margin of this study. With regard to cellularity, contamination, bloodiness score, diagnostic ability, and diagnostic accuracy, there were no significant differences between both groups. There were no dropouts in the study. Limitations A variety of target lesions, multiple pathologists, lack of an assessment of intraobserver and interobserver variability, and a single-blind study for the pathologists. Conclusion EUS-FNA S− is noninferior to EUS-FNA S+ on histological assessment. (Clinical trial registration number: UMIN000008695.)

We sought to evaluate whether pancreatic elasticity, measured using acoustic radiation force impulse (ARFI) imaging, can determine the degree of pancreatic fibrosis and risk of pancreatic fistula (PF) in patients undergoing pancreatic resection. Although soft pancreatic texture is a reliable predictor of postoperative PF, noninvasive, quantitative methods of assessing pancreatic hardness have not been established.Shear wave velocity (SWV) of the pancreas was preoperatively measured by ARFI imaging in 62 patients undergoing pancreatic resection. Correlations of SWV with pathologic degree of fibrosis in the resected pancreas, exocrine function of the remnant pancreas, and the incidence of postoperative PF were determined.The SWV was positively correlated with the degree of pancreatic fibrosis (Spearman's rank correlation coefficient [ρ] = 0.660, p0.001) and inversely correlated with postoperative amylase concentrations and daily output of pancreatic juice. The incidence of postoperative PF was significantly higher in the 32 patients with soft (SWV1.54 m/s) than in the 30 with hard (SWV ≥ 1.54 m/s) pancreata (63% vs 17%, p0.001). Multivariate analysis showed that a soft pancreas (SWV1.54 m/s) was an independent predictor of postoperative PF (odds ratio 38.3; 95% CI 5.82 to 445; p = 0.001).Pancreatic elasticity on preoperative ARFI imaging accurately reflected the pathologic degree of fibrosis and exocrine function of the pancreas, enabling surgeons to adopt appropriate surgical procedures according to the risk of postoperative PF in each patient undergoing pancreatic resection.

Esophageal adenocarcinomas usually develop in Barrett's esophagus, typically through the metaplasia-dysplasia-carcinoma sequence, but adenocarcinomas can occur from heterotopic gastric mucosa in cervical esophagus (inlet patch). This report describes the first case of synchronous presentation of adenocarcinoma arising from cervical inlet patch and Barrett's esophagus-related dysplasia in a 76-year-old man. Surveillance CT detected a 3-cm polypoid mass in the cervical esophagus. Endoscopic biopsies confirmed a diagnosis of adenocarcinoma of the cervical esophagus. Barrett's esophagus was present also in the lower esophagus. Histologic examination of the surgically resected specimen revealed the polypoid mass as composed of tubular adenocarcinoma, and was associated with non-neoplastic columnar mucosa representing pre-existing inlet patch. Another isolated cervical inlet patch with intestinal metaplasia was also recognized. In the lower esophagus, high-grade dysplasia was noted within the Barrett's esophagus. Immunohistochemically, the adenocarcinoma associated with inlet patch had intestinal immunophenotype (CDX2-, CD10- and MUC2-positive), whereas the Barrett's esophagus-related high-grade dysplasia showed mixed immunophenotype (MUC5AC- and MUC6-positive, with scattered MUC2-positive goblet cells). Previous studies and our findings suggest that intestinal metaplasia might predispose to the development of adenocarcinoma in the inlet patch. Therefore, endoscopists and pathologists should be aware of rare malignant transformation of inlet patches, especially those with intestinal metaplasia.

Kruppel-like factor 4 (KLF4) is a zinc-finger-type transcription factor with a restricted expression pattern during skeletal development. We have previously shown that KLF4 represses osteoblast mineralization concomitant with a down-regulation in the expression of a number of osteoblastic genes, both in vivo and in vitro. In addition to the cell-autonomous effects of KLF4 in osteoblasts, transgenic osteoblastic-KLF4 mice show severe defects in osteoclast maturation. Wild-type bone-marrow-derived macrophages co-cultured with KLF4-expressing osteoblasts exhibit reduced formation of multinuclear osteoclasts as compared with control cultures overexpressing green fluorescent protein. Significantly, the transduction of Runx2, a master regulator of osteoblastogenesis, together with KLF4 into osteoblasts restores the reduction in osteoclastogenesis induced by KLF4 alone. Various extracellular matrix molecules are down-regulated by KLF4 overexpression but this down-regulation can be partially restored by the co-transduction of Runx2. These results suggest that osteoblastic-KLF4 affects osteoclast maturation by regulating cell-matrix interactions and reinforce the importance of the regional down-regulation of KLF4 expression in the subset of osteoblasts for normal skeletal modeling and remodeling.

Mechanical stress induces various hypertrophic responses including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Here we examined the role of the small GTP-binding proteins of Rho family and reactive oxygen species (ROS) in stretch-induced activation of p38MAPK in cardiomyocytes. Overexpression of dominant-negative mutants of Rac1 (D.N. Rac1), D.N.RhoA and D.N.Cdc42 suppressed stretch-induced activation of p38MAPK. Overexpression of constitutively active mutants of Rac1 (C.A.Rac1) and C.A.Cdc42 increased the p38MAPK activity in the absence of mechanical stress. Pretreatment with N-acetyl- l -cysteine and N-(2-mercaptopropionyl)-glycine (NAC) suppressed stretch-induced activation of p38MAPK. Mechanical stretch increased intracellular ROS generation, which was abrogated by overexpression of D.N.Rac1 and attenuated by overexpression of D.N.RhoA and D.N.Cdc42. An increase in protein synthesis evoked by mechanical stretch was suppressed by overexpression of D.N.Rac1 and pretreatment with NAC. These results suggest that mechanical stress induces cardiac hypertrophy through the Rac1-ROS-p38MAPK pathway in cardiac myocytes.

Background and Aims: Pancreatic ductal adenocarcinoma (PDAC) is well characterized by dense fibrotic stroma with abundant cancer-associated fibroblasts (CAFs). As CAFs are activated during tumorigenesis and acquire tumor-promoting properties, activated CAFs have been implicated in PDAC progression; however, the precise mechanisms of their activation remain largely unknown. The bromodomain and extraterminal (BET) domain proteins are epigenetic reader proteins that recognize acetylated amino acid residues on histone tails and facilitate gene transcription. Recent studies have demonstrated therapeutic efficacy of BET inhibitors on various cancers including PDAC, mainly through suppression of c-myc transcription; however, how BET inhibitors suppress PDAC growth and their effects on CAFs remains largely unknown. Using patient-derived tumor xenografts (PDX) and primary CAFs, we investigated the therapeutic efficacy and dissected the underlying mechanisms of a BET inhibitor, JQ1, on human PDAC and CAFs. Methods: We established PDX lines and primary CAFs from surgically resected human PDAC specimen. For in vivo analyses, mice bearing subcutaneous tumor were treated with vehicle or JQ1. For in vitro analyses, patient-derived PDAC cells and CAFs were treated with vehicle or JQ1 and analyzed separately. To explore the pro-tumorigenic role of secretion from CAFs, PDAC cells were cultured with conditioned medium (CM) that was collected from DMSO- or JQ1- treated CAFs. Chromatin immunoprecipitation (ChIP) assay was performed to assess the binding of transcription factors and histone modifications which are associated with altered gene expression in CAFs by JQ1 treatment. Results: In vivo experiments revealed that volumes and weights of subcutaneous PDX tumors were significantly smaller in JQ1-treated mice than vehicle-treated mice. Unexpectedly, however, JQ1 exerted only minimal effects to the proliferation of PDAC cells that were isolated from PDX tumors and cultured in vitro, suggesting the involvement of cell-extrinsic mechanisms in the JQ1-mediated suppression of tumor growth in vivo. Of note, histopathological analysis of PDX tumors revealed that JQ1 treatment dramatically ameliorated desmoplastic change, with reduction in extracellular matrix (ECM) deposition and α-SMA expressing CAFs. As α-SMA expression and ECM production is a hallmark of activated CAFs, we hypothesized that JQ1 might inactivate CAFs, thereby reducing their tumor-promoting properties. To test this hypothesis, qPCR was performed to analyze gene expression in primary CAFs cultured in vitro and also in stromal cells in PDX tumors in vivo. As expectedly, JQ1 suppressed the expression of genes implicated in the properties of activated CAF, including ECM, cytokines and growth factors both in vitro and in vivo. Furthermore, when PDAC cells were cultured with CM from DMSO–treated CAFs, proliferation of PDAC cells were promoted along with activation of MAPK, AKT, and STAT3 pathways, which was abrogated when cultured with CM from JQ1-treated CAFs. Consistently, immunoblotting and immunohistochemistry of PDX tumors demonstrated that JQ1 reduced phosphorylation of ERK, AKT, and STAT3 in PDAC cells in vivo. Mechanistically, we found that JQ1 suppressed hedgehog and TGF-β/SMAD3 pathways, both of which play central roles in CAF activation, through disruption of BRD4 recruitment to the promoter regions of their target genes. Conclusions: BET proteins are critical regulators of CAF-activation in PDAC. Inactivation of CAFs by BET inhibition offers a novel therapeutic approach for PDAC. Citation Format: Keisuke Yamamoto, Keisuke Tateishi, Yotaro Kudo, Mayumi Hoshikawa, Mariko Tanaka, Takuma Nakatsuka, Hiroaki Fujiwara, Koji Miyabayashi, Ryota Takahashi, Yasuo Tanaka, Hideaki Ijichi, Yousuke Nakai, Hiroyuki Isayama, Yasuyuki Morishita, Taku Aoki, Yoshihiro Sakamoto, Kiyoshi Hasegawa, Norihiro Kokudo, Masashi Fukayama, Kazuhiko Koike.{Authors}. BET inhibition remodels tumor stroma and suppresses progression of human pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B66.

何らかの原因で転倒しそうになった際,下肢を踏み出して転倒を防ぐ反応が起こる。高齢者ではその反応の時間の延長が転倒につながると考えられる。本研究では,若年成人,過去に転倒を経験していない高齢者および転倒を経験した高齢者の3群を対象として,立位姿勢で光刺激を合図に右下肢を前方に踏み出してもらい,その際の下肢の反応時間および運動時間を測定し,各群の比較を行い,転到との関連性を検討した。その結果、転倒経験を持つ高齢者では下肢運動時間が延長していたが、premotor timeとmotor timeでは転倒経験のある高齢者とない高齢者では有意差は認められなかった。高齢者の転倒は下肢運動時間と関係があることが示唆された。

Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic masses is an established procedure for obtaining a pathological specimen. However, application of suction during EUS-FNA is still controversial and the efficacy of the slow-pull technique was recently reported for new core biopsy needles.The purpose of this study was to compare the suction and slow-pull techniques using regular FNA needles.The diagnostic yield of the suction and slow-pull techniques was retrospectively studied for patients who underwent EUS-FNA for pancreatic solid lesions.A total of 367 passes (181 by suction and 186 by the slow-pull technique) were performed during 97 EUS-FNA procedures for 93 patients with pancreatic solid lesions. The slow-pull technique resulted in lower scores for cellularity (≥2 for 37.5 % vs. 76.7 %) but scores for contamination with blood were lower (≥2 for 25.0 % vs. 66.7 %) and sensitivity of diagnosis of malignancy was higher (90.0 % vs. 67.9 %) when a 25-gauge FNA needle was used. There were no significant differences between the two techniques when a 22-gauge needle was used. In multivariate analysis of 82 cases with malignancy, the slow-pull technique (odds ratio (OR) 1.92, P = 0.028), tumor size ≥25 mm (OR 4.64, P0.001), and tumor location in the body or tail (OR 2.82, P0.001) were associated with greater sensitivity.The slow-pull technique was associated with less contamination with blood and can potentially increase the diagnostic yield compared with the suction technique in EUS-FNA of pancreatic solid masses, especially with a 25-gauge FNA needle.

Primary adrenal lymphoma is a rare subtype observed in only 0.83% of all non-Hodgkin lymphoma [1], although the adrenal gland may be involved in up to 25% of NHL cases, by autopsy [2]. The immunoph...

NICUで管理されるハイリスク新生児の難聴の発生頻度は一般の頻度と比べ高率であるとされ, 早期発見のためにABR等を使った聴力スクリーニングを行っている施設が多い。1990-1995年の6年間に行った329名のABRについて検討した結果33名10.0%がABR異常で, その重要な因子は (1) 10日間以上の長期人工呼吸管理 (2) 脳障害 (3) 頭頸部奇形 (4) 奇形症候群 (5) PPHN (6) 妊娠中の非細菌感染 (7) 1,000g未満の超低出生体重の各因子であった。またこの6年間に初回ABRが正常であったのに, 後に高度難聴と診断された例が4例あり, うち3例は長期人工呼吸管理を受け, high frequency oxygenation (HFO) を使用されていた。また2例にはPPHNも合併していた。こういった後に発症した難聴も見逃さない方法として, NICUを退院した全員に1歳前後にCORを行う方法を提唱する。

The incidence of deep neck infection has decreased with the development of antibiotics. However, treatment still requires careful consideration, since delays in treatment may cause severe complications, such as septic shock or DIC leading to death. Twenty-three cases of deep neck infection which occurred over a 13-year period were evaluated. Surgical treatment was applied in 11 of the 23 cases. A total of 10 cases (71.4%) out of the 14 cases of abscess which were incised resulted in good recovery. In 2 of the remaining 4 cases who underwent conservative treatments for deep neck abscess, both of which had gas formation, secondary mediastinitis, and systemic disease such as diabetes, ultimately contributed to death.These results strongly support the conclusion that it is necessary to use appropriate surgical treatment in combination with antibiotic therapy to control systemic disease, but conservatlve therapy alone is in sufficient, in the management of severe deep neck abscess with gas formation, mediastinitis, and systemic disease such as diabetes.

運動療法を処方した骨粗鬆症患者に運動継続に関するアンケートを実施した。調査対象は骨粗鬆症と診断され，1年以上運動療法を継続している全女性50名に質問紙法による郵送調査をおこなった。回答が得られたのは35名（回収率70%）であった。アンケート内容は（1）運動実施の状況（2）運動の効果と予防の意識（3）運動の中断ならび中止の理由についてであった。二次予防における運動継続率は54%と低かったが，予防に対する意識は強く，運動の継続により健康に対する意識を変化させ，生活に積極性をもたらすことが可能であると考察した。運動継続の要因については，開始初期において運動に対する身体的，心理的，社会的効果を理解しているかどうかが重要である。そのためには運動に対する動機づけが大切であり運動の必要性，効果について繰返し説明し，理解を得るよう治療者側が配慮することが，動機づけをより高めることにつながると考えられる。

Aims Mucinous borderline tumours of the ovary are subclassified as intestinal-type (IMBT) and endocervical-like (EMBT), which differ in their clinicopathological features. In this study, we attempted to elucidate characteristics of the mucinous epithelium in each subtype. Methods and results The expression of claudin-18, a marker of gastric differentiation, MUCs, CDX2, CK7, CK20, oestrogen receptor (ER), progesterone receptor (PgR), CA-125 and vimentin in IMBTs (n = 54), EMBTs (n = 25) and serous borderline tumours (SBTs) (n = 22) were compared by immunohistochemistry. Claudin-18 positivity was identified in 98% of the IMBTs, whereas only 4% of the EMBTs were claudin-18-positive. Expression of intestinal markers such as CDX2 and MUC2 was relatively infrequent in IMBTs (48% and 33%, respectively). Mullerian-lineage markers such as ER, PgR and vimentin were expressed rarely in IMBTs, while most EMBTs and SBTs were positive for these markers. Hierarchial clustering revealed a close association between EMBTs and SBTs, while IMBTs were clearly separate. Conclusions Claudin-18 positivity is a specific phenotype that is characteristic of IMBTs. Frequent and diffuse expression of gastric markers, along with less frequent and usually focal expression of intestinal markers, suggests that IMBTs are essentially composed of gastrointestinal-type mucinous epithelium (gastric-type epithelium with a variable degree of intestinal differentiation).